U.S. patent application number 13/255202 was filed with the patent office on 2011-12-29 for thiazole derivative and process for producing same.
This patent application is currently assigned to GIFU UNIVERSITY. Invention is credited to Toshiaki Murai.
Application Number | 20110319616 13/255202 |
Document ID | / |
Family ID | 42728316 |
Filed Date | 2011-12-29 |
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United States Patent
Application |
20110319616 |
Kind Code |
A1 |
Murai; Toshiaki |
December 29, 2011 |
THIAZOLE DERIVATIVE AND PROCESS FOR PRODUCING SAME
Abstract
An object is to provide a thiazole derivative produced from
easily available raw materials by a simplified production process.
Provided are a process for producing a novel thiazole derivative
represented by the general formula (I), which is characterized by
adding a strong base to a thioamide represented by the general
formula (II) and reacting the mixture with a thioformamide
represented by the general formula (III), and a novel thiazole
derivative.
Inventors: |
Murai; Toshiaki; ( Gifu,
JP) |
Assignee: |
GIFU UNIVERSITY
Gifu-shi, Gifu
JP
|
Family ID: |
42728316 |
Appl. No.: |
13/255202 |
Filed: |
March 8, 2010 |
PCT Filed: |
March 8, 2010 |
PCT NO: |
PCT/JP2010/053765 |
371 Date: |
September 7, 2011 |
Current U.S.
Class: |
544/133 ;
544/160; 546/256; 546/262; 546/270.4; 546/280.4; 546/331; 548/190;
564/74; 564/78 |
Current CPC
Class: |
C07D 417/04 20130101;
C07D 417/14 20130101; C07D 277/18 20130101; C07D 277/42
20130101 |
Class at
Publication: |
544/133 ;
548/190; 546/270.4; 546/256; 564/78; 564/74; 544/160; 546/331;
546/262; 546/280.4 |
International
Class: |
C07D 417/04 20060101
C07D417/04; C07D 417/14 20060101 C07D417/14; C07C 327/42 20060101
C07C327/42; C07D 409/12 20060101 C07D409/12; C07D 295/194 20060101
C07D295/194; C07D 213/59 20060101 C07D213/59; C07D 401/12 20060101
C07D401/12; C07D 277/18 20060101 C07D277/18; C07C 327/48 20060101
C07C327/48 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 10, 2009 |
JP |
JP2009-055787 |
Claims
1. A process for producing a thiazole derivative represented by the
general formula (I), wherein a strong base is added to a thioamide
represented by the general formula (II) and the mixture is reacted
with a thioformamide represented by the general formula (III):
##STR00044## represents a single bond or a double bond; R.sup.1 is
selected from the group consisting of a branched or cyclic alkyl
group having 3 to 12 carbon atoms, an aryl group, and a
heteroaromatic group, and optionally each of the groups is
substituted with at least one group selected from the group
consisting of halogen, hydroxy, lower alkyl, lower alkoxy, and halo
lower alkyl; R.sup.2 represents an aryl group that is optionally
substituted with at least one group selected from the group
consisting of a halogen, hydroxy, lower alkyl, lower alkoxy, and
halo lower alkyl, and a pyridyl group, wherein the pyridyl group is
optionally substituted with at least one group selected from the
group consisting of halogen, hydroxy, lower alkyl, lower alkoxy,
and halo lower alkyl; R.sup.3 and R.sup.4 are the same or
different, and each R.sup.3 and R.sup.4 represents a group selected
from the group consisting of a linear, branched or cyclic alkyl
group having 1 to 12 carbon atoms, an aryl group, and a
heteroaromatic group, wherein each of the groups is optionally
substituted with one at least one group selected from the group
consisting of halogen, hydroxy, lower alkyl, lower alkoxy, and halo
lower alkyl, or R.sup.3 and R.sup.4 independently represent a
C.sub.5 to C.sub.7 heterocyclic ring formed together with a
nitrogen atom to which R.sup.3 and R.sup.4 are bonded; and Y
represents a hydrogen atom or ##STR00045##
2. The process for producing a thiazole derivative according to
claim 1, wherein the strong base is one or more selected from
n-butyllithium, lithium diisopropylamide, sodium hydride, potassium
hydride, potassium t-butoxide, calcium hydride, sodium hydroxide,
and sodium amide.
3. The process for producing a thiazole derivative according to
claim 1, wherein after reacting the thioformamide, iodine is
further added and the mixture is reacted.
4. A thiazole derivative represented by the general formula (IV):
##STR00046## wherein R.sup.1 is selected from the group consisting
of a branched or cyclic alkyl group having 3 to 12 carbon atoms, an
aryl group, and a heteroaromatic group, and each of the groups is
optionally substituted with at least one group selected from the
group consisting of halogen, hydroxy, lower alkyl, lower alkoxy,
and halo lower alkyl, and Y represents ##STR00047## and R.sup.3 and
R.sup.4 are the same or different, and each is selected from the
group consisting of a linear, branched or cyclic alkyl group having
1 to 12 carbon atoms, an aryl group, and a heteroaromatic group
wherein each of the groups is optionally substituted with at least
one substituent selected from the group consisting of halogen,
hydroxy, lower alkyl, lower alkoxy, and halo lower alkyl, or
R.sup.3 and R.sup.4 is independently a C.sub.5 to C.sub.7
heterocyclic ring formed together with a nitrogen atom to which
R.sup.3 and R.sup.4 are bonded.
5. A thiazole derivative represented by the general formula (V):
##STR00048## wherein R.sup.1 is a group selected from the group
consisting of a branched or cyclic alkyl group having 3 to 12
carbon atoms, an aryl group, and a heteroaromatic group, and each
of the groups is optionally substituted with at least one
substituent selected from the group consisting of halogen, hydroxy,
lower alkyl, lower alkoxy, and halo lower alkyl, and R.sup.5 and
R.sup.6 are the same or different, and each represents a group
selected from the group consisting of a linear, branched or cyclic
alkyl group having 1 to 12 carbon atoms, an aryl group, and a
heteroaromatic group, wherein each of the groups is optionally
substituted with at least one substituent selected from the group
consisting of halogen, hydroxy, lower alkyl, lower alkoxy, and halo
lower alkyl, and at least one of R.sup.5 and R.sup.6 is an aryl
group, wherein the aryl group is optionally substituted with at
least one substituent selected from the group consisting of
halogen, hydroxy, lower alkyl, lower alkoxy, and halo lower alkyl,
and a heteroaromatic group, wherein the heteroaromatic group is
substituted with at least one substituent selected from the group
consisting of halogen, hydroxy, lower alkyl, lower alkoxy, and halo
lower alkyl.
6. The process for producing a thiazole derivative according to
claim 2, wherein after reacting the thioformamide, iodine is
further added and the mixture is reacted.
7. A thiazole IA or dihydro-thiazole IB of the formula ##STR00049##
wherein each R.sup.1 group is the same or different and is selected
from the group consisting of a linear, branched or cyclic alkyl
group of 1 to 12 carbon atoms, an aryl group and a heteroaromatic
group, wherein each said group comprises at least one H atom, a
halogen atom, a hydroxyl group, an alkyl group of 1 to 6 carbon
atoms, or an alkoxy group of 1 to 6 carbon atoms, wherein each
R.sup.2 is the same or different and is selected from the group
consisting of a hydrogen atom, a halogen atom, a hydroxyl group, an
alkyl group of 1 to 6 carbon atoms, an alkoxy group of 1 to 6
carbon atoms, and an aryl group, wherein the aryl group is selected
from the group consisting of an aryl alkyl group of 1 to 6 carbon
atoms, an aryl alkyl halo group of 1 to 6 carbon atoms, an aryl
halo group, an aryl hydroxyl group, aryl alkyl alkoxy group of 1 to
6 carbon atoms, a halo thiophenyl group, and a halo pyridyl group,
and wherein each Y is the same or different and is selected from
the group consisting of a hydrogen atom and a --NR.sup.3R.sup.4
group, wherein each R.sup.3 and R.sup.4 is the same or different
and is selected from the group consisting of a linear, branched or
cyclic alkyl group of 1 to 12 carbon atoms, or each R.sup.3 and
R.sup.4 in the same molecule is optionally connected to form a
C.sub.5 to C.sub.7 heterocyclic ring; and salts thereof.
8. A reactive composition for forming a thiazole derivative,
comprising: thiamides represented by the structures II and III
##STR00050## wherein each R.sup.1 group is the same or different
and is selected from the group consisting of a linear, branched or
cyclic alkyl group of 1 to 12 carbon atoms, an aryl group and a
heteroaromatic group, wherein each said group comprises at least
one H atom, a halogen atom, a hydroxyl group, an alkyl group of 1
to 6 carbon atoms, or an alkoxy group of 1 to 6 carbon atoms,
wherein each R.sup.2 is the same or different and is selected from
the group consisting of a hydrogen atom, a halogen atom, a hydroxyl
group, an alkyl group of 1 to 6 carbon atoms, an alkoxy group of 1
to 6 carbon atoms, an aryl group, wherein the aryl group is
selected from the group consisting of an aryl alkyl group of 1 to 6
carbon atoms, an aryl alkyl halo group of 1 to 6 carbon atoms, an
aryl halo group, an aryl hydroxyl group, aryl alkyl alkoxy group of
1 to 6 carbon atoms, a halo thiophenyl group, and a halo pyridyl
group, and wherein each R.sup.3 and R.sup.4 group is the same or
different and is selected from the group consisting of a linear,
branched or cyclic alkyl group of 1 to 12 carbon atoms, or each
R.sup.3 and R.sup.4 group in the same molecule is optionally
connected to form a C.sub.5 to C.sub.7 heterocyclic ring; and salts
thereof.
9. The reactive composition for forming a thiazole derivative of
claim 8, wherein when R.sup.2 is an aryl group, dihydrothiazole
represented by the following general formula (IV) is selectively
obtained, and wherein when R.sup.2 is a pyridyl group, thiazole
represented by the following general formula (VI) is selectively
obtained: ##STR00051##
10. The reactive composition for forming a thiazole derivative of
claim 8, comprising iodine.
11. A method of making a thioamide, comprising: combining compounds
represented in formula 4 ##STR00052## wherein R.sup.1 is a group
selected from the group consisting of a branched or cyclic alkyl
group having 3 to 12 carbon atoms, an aryl group, and a
heteroaromatic group, and wherein each R.sup.1 is optionally
substituted with at least one substituent selected from the group
consisting of halogen, hydroxy, lower alkyl, lower alkoxy, and halo
lower alkyl, wherein the branched alkyl group includes isopropyl,
isobutyl and t-butyl, wherein the cyclic alkyl group includes
cyclopropyl and cyclohexyl, wherein the aryl group includes benzyl,
tolyl and xylyl, and wherein the heteroaromatic group includes
pyridyl, furyl and thienyl, wherein R.sup.2 represents an aryl
group that is optionally substituted with at least one substituent,
or a pyridyl group that is optionally substituted at least one
substituent, wherein each substituent of the aryl group is the same
or different and is selected from the group consisting of a halogen
atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms,
an alkoxy group having 1 to 6 carbon atoms, and an alkoxycarbonyl
group having 1 to 6 carbon atoms, respectively, or wherein each
substituent of the pyridyl group is the same or different and is
selected from the group consisting of a halogen atom, a hydroxyl
group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group
having 1 to 6 carbon atoms, and an alkoxycarbonyl group having 1 to
6 carbon atoms.
12. The method of claim 11, wherein the range of molar ratios of an
aldehyde group-containing compound: sulfur: amino group-containing
compound is 1:1:1 to 1:1.2:1.2.
Description
TECHNICAL FIELD
[0001] The present invention relates a thiazole derivative and a
process for producing the same. More specifically, the present
invention relates to a process for producing a pyridyl thiazole
compound or a dihydrothiazole compound at a high yield,
inexpensively, simply and selectively.
BACKGROUND ART
[0002] A thiazole derivative is a useful compound as a functional
compound (or a synthesis intermediate thereof) such as an
agricultural chemical (insecticide, etc.), a medical product, a
fungicide and a dye, and an electronic material. Examples thereof
include a thiazole derivative that is a compound having a thiazole
skeleton used as an interleukin-6 production inhibitor/bone
absorption inhibitor/anti-osteoporosis agent (Patent Document 1), a
thiazole derivative used as a bone forming accelerator (Patent
Document 2), a thiazole derivative used as a protein kinase C
inhibitor (Patent Document 3), a thiazole derivative used as an
agricultural chemical intermediate (Patent Document 4), and a
thiazole derivative used as a neuropeptide Y antagonist (Patent
Document 5).
[0003] In these documents, various methods are disclosed as
synthesis examples of thiazole derivatives. For example, bromine is
dropped into a dichloromethane solution of 4'-chloropropiophenone
to be acted and the mixture is then reacted with thiourea (Patent
Documents 1 and 2), a method of adding 3-chloroacetylacetone to an
ethanol solution of thiourea and reacting with heating, and then
adding a poor solvent to be deposited by cooling (Patent Document
3), a method of mixing difluorophenacyl bromide and
cyanothioacetoamide in water to be reacted with heating (Patent
Document 4), and a method of mixing .beta.-acetonaphtone and
thiourea, and tetrabutylammonium bromide in ethyl acetate and
dropping bromine thereinto to be reacted (Patent Document 6). These
methods respectively remain rooms for improvements with respect to
using bromine that has a pungent odor, with respect to necessity of
obtaining particular reagents, and the like.
[0004] On the other hand, a pyridyl thiazole compound that is one
of thiazole derivatives is useful as a fungicidal composition, and
a production process thereof is described in the following document
(Patent Document 7). According to the document, 2,6-dibromopyridine
is treated with alkyl lithium and N,N-dimethyl acetoamide is then
added thereto. The reaction mixture is brominated with a
brominating agent in the presence of an acid and then reacted with
thioacetamide and, finally by a coupling reaction with alkyl
halogen, a desired pyridyl thiazole compound is thus obtained. This
process includes a step with multiple stages and thus has a problem
with respect that an operation method thereof is somewhat
complicated.
[0005] Furthermore, for a preparation process of dihydrothiazole
(referred to as thiazoline in IUPAC, and referred to as
dihydrothiazole in order to clarify difference from thiazole in the
present invention) that is one of thiazole derivatives, proposed
is, for example, a method of mixing methyl
2-(difluoromethyl)-5-(((2-chloroethyl)amino)carbonyl)-4-(2-methylpropyl)--
6-trifluoromethyl)-3-pyridinecarboxylate and diphosphorus
pentasulfide with heating and degassing to produce dihydrothiazole
(Patent Document 8). In this method, a particular starting
substance is required in order to obtain a 4,5-dihydrothiazole
compound having a pyridyl group at the 2nd position.
PRIOR ART DOCUMENTS
Patent Documents
[0006] Patent Document 1: Japanese Unexamined Patent Application
Publication (JP-A) No. Hei10-87490 [0007] Patent Document 2: JP-A
No. Hei11-209284 [0008] Patent Document 3: JP-A No. 2002-53566
[0009] Patent Document 4: Domestic re-publication of PCT
application No. WO2002/094798 [0010] Patent Document 5: Japanese
Unexamined Patent Application Publication (Translation of PCT
Application) No. 2006-502131 [0011] Patent Document 6: JP-A No.
2006-225334 [0012] Patent Document 7: JP-A No. Hei5-194506 [0013]
Patent Document 8: JP-A No. Hei11-269174
DISCLOSURE OF INVENTION
Problems to be Solved by the Invention
[0014] As described above, a thiazole derivative is very useful as
an intermediate of a functional material such as a pharmaceutical
composition and a dye, and an electronic material; however, in a
conventional synthesis method, there has been considered to have a
room for improvements such as particularity of raw materials to be
used and necessity of production steps with multiple stages.
Therefore, an object in the present invention is to propose a
simplified production process using easily available raw
materials.
Means for Solving the Problems
[0015] As a result of intensive studies made in order to solve the
above described problems and achieve the desired object, it was
found in the present invention that when a thioamide is synthesized
and then acted with a thioformamide through a thioamide dianion,
thiazole or dihydrothiazole can be selectively synthesized by a
substituent of the thioamide.
[0016] That is, the present invention relates to a process for
producing a thiazole derivative represented by the general formula
(I), wherein a strong base is added to a thioamide represented by
the general formula (II) and the mixture is then reacted with a
thioformamide represented by the general formula (III):
##STR00001##
[0017] represents a single bond or a double bond, R1 represents a
group selected from a branched or cyclic alkyl group having 3 to 12
carbon atoms, an aryl group, and a heteroaromatic group, and each
of the groups may be further substituted with one or more
substituents selected from halogen, hydroxy, lower alkyl, lower
alkoxy, and halo lower alkyl;
[0018] R.sup.2 represents an aryl group that may be substituted
with one or more substituents selected from halogen, hydroxy, lower
alkyl, lower alkoxy, and halo lower alkyl, or a pyridyl group that
may be substituted with one or more substituents selected from
halogen, hydroxy, lower alkyl, lower alkoxy, and halo lower
alkyl;
[0019] R.sup.3 and R.sup.4 are the same or different, and each
represents a group selected from a linear, branched or cyclic alkyl
group having 1 to 12 carbon atoms, an aryl group, and a
heteroaromatic group (wherein each of the groups may be further
substituted with one or more substituents selected from halogen,
hydroxy, lower alkyl, lower alkoxy, and halo lower alkyl), or
R.sup.3 and R.sup.4 represent a C.sub.5 to C.sub.7 heterocyclic
ring formed together with a nitrogen atom to which R.sup.3 and
R.sup.4 are bonded; and Y represents a hydrogen atom or
##STR00002##
[0020] It is characterized in that when R.sup.2 is an aryl group,
dihydrothiazole represented by the following general formula (IV)
is selectively obtained, and when R.sup.2 is a pyridyl group,
thiazole represented by the following general formula (VI) is
selectively obtained:
##STR00003##
[0021] R.sup.1 in the above formula is the same as a group
represented in the general formula (I) and the general formula
(II), and Y is the same as a group represented in the general
formula (I).
[0022] Such a selective reaction has not been known at all so far,
and the reaction mechanism thereof will be specifically described
later. A desired thiazole derivative can be synthesized according
to this selectivity, which thus makes it possible to obtain broad
candidate compounds including applications and functions in the
pharmaceutical field and the basic material field by a simple
method.
[0023] Examples of a strong base added to a thioamide represented
by the general formula (II) include n-butyllithium, lithium
diisopropylamide, sodium hydride, potassium hydride, potassium
t-butoxide, calcium hydride, sodium hydroxide, and sodium amide.
These strong bases act on carbon adjacent to the nitrogen atom in
the thioamide to extract hydrogen and form a thioamide dianion.
n-butyllithium is preferably used as a strong base.
[0024] Further, dihydrothiazole as represented by the general
formula (IV) is a totally novel compound in which an amino group is
bonded to the 5th position in a thiazoline ring. Thiazoline has
been known as an intermediate of a medical drug or an agricultural
chemical and, in the present invention, an amino group and a phenyl
group are respectively bonded instead of a conventional hydrogen
atom and the 4th and 5th positions become asymmetric carbons, and
thus, a new possibility for an optical activity can also be
searched.
[0025] In addition, a thioformamide represented by the general
formula (III) is reacted and iodine is then added thereto to be
reacted, thereby enabling to obtain a thiazole derivative
represented by the following general formula (V), other than
dihydrothiazole represented by the general formula (IV).
##STR00004##
[0026] In the formula, R.sup.1 is the same as a group shown in the
general formula (I). R.sup.5 and R.sup.6 are the same or different,
and each represents a group selected from a linear, branched or
cyclic alkyl group having 1 to 12 carbon atoms, an aryl group, and
a heteroaromatic group (wherein each of the groups may be further
substituted with one or more substituents selected from halogen,
hydroxy, lower alkyl, lower alkoxy, and halo lower alkyl), or at
least one of R.sup.5 and R.sup.6 represents an aryl group that may
be substituted with one or more substituents selected from halogen,
hydroxy, lower alkyl, lower alkoxy, and halo lower alkyl, or a
heteroaromatic group that may be substituted with one or more
substituents selected from halogen, hydroxy, lower alkyl, lower
alkoxy, and halo lower alkyl.
[0027] A thiazole derivative represented by the general formula (V)
has intensive fluorescence emission particularly when R.sup.5 and
R.sup.6 are aryl groups, that is, the 5th position in a thiazole
ring is a diarylamino group, and is a compound that can be expanded
to an electron transfer layer, and the like in an organic
electroluminescence element (hereinafter electroluminescence is
abbreviated as "EL").
Effect of the Invention
[0028] The method for producing a thiazole derivative of the
present invention can simply and easily produce a thiazole
derivative from easily available, inexpensive raw materials without
undergoing a complicated synthesis path, which thus can achieve to
reduce synthesis cost. Furthermore, for a synthesized product,
specifying a substituent of a thioamide makes it possible to obtain
a generated product selectively, and also, a totally novel compound
that has never existed so far can be easily obtained; therefore,
the obtained thiazole derivative can bring significant contribution
to creation of a novel compound useful as medical drugs and
agricultural chemicals, etc.
[0029] Furthermore, addition of iodine to a reaction system enables
to obtain a thiazole derivative having extension in a conjugated
system, and broad applications for development of new electronic
materials can be expected.
BRIEF DESCRIPTION OF DRAWINGS
[0030] FIG. 1 is a view showing a fluorescence spectrum for one
example of the thiazole derivative of the present invention
(Example 6).
MODES FOR CARRYING OUT THE INVENTION
[0031] The production process of the present invention will be more
specifically described below.
[0032] The present invention is characterized by adding a strong
base to a thioamide and then reacting the mixture with a
thioformamide, and the following reaction formula (a) can be
utilized as one example of a synthesis method of the thioamide:
##STR00005##
[0033] In the formula, R.sup.1 represents a group selected from a
branched or cyclic alkyl group having 3 to 12 carbon atoms, an aryl
group, and a heteroaromatic group, and each of the groups may be
further substituted with one or more substituents selected from
halogen, hydroxy, lower alkyl, lower alkoxy, and halo lower alkyl.
Examples of such a branched alkyl group include isopropyl, isobutyl
and t-butyl, examples of a cyclic alkyl group include cyclopropyl
and cyclohexyl, examples of an aryl group include benzyl, tolyl and
xylyl, and examples of a heteroaromatic group include pyridyl,
furyl and thienyl. These groups are preferable because of high
yield when a thioamide dianion is formed by a reaction with a
strong base.
[0034] R.sup.2 in the formula represents an aryl group that may be
substituted with one or more substituents, or a pyridyl group that
may be substituted with one or more substituents. More
specifically, R.sup.2 represents a group selected from a phenyl
group that may be substituted with 1 or 2 groups selected from a
halogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon
atoms, an alkoxy group having 1 to 6 carbon atoms, and an
alkoxycarbonyl group having 1 to 6 carbon atoms, respectively, or a
pyridyl group that may be substituted with 1 or 2 groups selected
from a halogen atom, a hydroxyl group, an alkyl group having 1 to 6
carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and an
alkoxycarbonyl group having 1 to 6 carbon atoms, respectively,
which is a group being a key to selectively synthesizing the
thiazole derivative of the present invention.
[0035] The above described reaction formula (a) is a method
conventionally known as a synthesis method of thioamide that is a
starting substance of the present invention. This method is
characterized in that any of the raw materials (compounds in the
left side of the formula) can be easily and inexpensively obtained,
structure design of a thioamide can be freely performed as a result
thereof, and the like. However, R.sup.2 is used selectively in the
present invention for synthesis of a desired thiazole
derivative.
[0036] In this reaction, dimethylformamide, dimethylsulfoxide,
N-methylpyrrolidone, toluene, and the like can be used as an
organic solvent. Among these substances, when a thioamide is once
purified and then isolated and stored, etc., dimethylformamide is
preferable from the viewpoint that a generated product is easily
separated in a process of washing a reaction system with water.
[0037] In addition, this reaction is performed at 60 to 110.degree.
C., and preferably 80 to 90.degree. C. When the reaction is
preformed at a lower temperature than the above temperature, a
reaction speed is lowered and a yield tends to decrease, and when
the reaction is performed at a higher temperature, a side reaction
easily occurs and there is a possibility to take trouble in
purification.
[0038] The above reaction can be performed within the range of
molar ratios of an aldehyde group-containing compound: sulfur:
amino group-containing compound=1:1:1 to 1:1.2:1.2. The most
preferable ratio among these is 1:1.1:1.1, since an aldehyde
group-containing compound is completely reacted and purification of
a thioamide is effectively promoted. In addition, this reaction is
called the Willgerodt-Kindler reaction and described in detail in
the document (Brown, E. V. Synthesis 1975, 358).
[0039] A synthesis path of dihydrothiazole when a compound having a
phenyl group for R.sup.2 is used as the above described amino
group-containing compound will be shown below:
##STR00006##
[0040] The upper reaction of the above described reactions is to
generate a thioamide dianion. Specifically, the reaction is a
reaction disclosed in the document (Murai, T. et al., J. Org. Chem.
2005, 70, 8153), etc. A point to remember in initiation of this
reaction is necessity to perform the reaction in an inert gas
atmosphere such as nitrogen or argon under a dehydrated condition.
A thioamide dianion obtained by reacting with a strong base has a
possibility for being easily dissolved due to presence of water or
oxygen, and is made stably exist to transfer to the next reaction.
In addition, lithium diisopropylamide, sodium hydride, potassium
hydride, potassium t-butoxide, calcium hydride, sodium hydroxide,
sodium amide, and the like can also be used as other strong bases,
and butyllithium (nBuLi) is preferable from the viewpoints of
reactivity, price, and availability. Furthermore, use of
butyllithium leads to an advantage such that separation is easy as
a butane gas after the reaction.
[0041] Tetrahydrofuran is used as a solvent in the above described
reaction. Toluene and diethyl ether, and the like can also be used
as other solvents, but the former has a possibility of slight
progress of a side reaction and the latter has a possibility that a
reaction intermediate is precipitated without being dissolved to
decrease a reaction yield, and thus, tetrahydrofuran is preferable.
The reaction can be carried out within the reaction temperature
range from -78.degree. C. to room temperature, and around 0.degree.
C. is suitable in consideration of suppression of a side reaction
and efficiency.
[0042] A mixing ratio of each compound to be reacted cannot be
clearly determined depending on compounds to be used, and
generally, about 2 equivalent amount of nBuLi is added to a
thioamide and then about 1 equivalent amount of a thioformamide is
added thereto. The thioamide and nBuLi generate a dianion in a
reaction with a ratio of 1:2, and the reaction progresses at almost
100% yield. Furthermore, since the generated dianion has high
activity, a reaction at almost 100% with the thioformamide occurs.
Therefore, a molar ratio of respective compounds is basically
thioamide:nBuLi:thioformamide=1:2:1.
[0043] In the lower stage of the above described reactions, a
thiazole skeleton is formed by a cyclization reaction in a
molecule. In addition, due to a thioformamide used in this
reaction, dihydrothiazole introduced with an amino group at the 5th
position, which has never been known so far, is obtained. Both of
carbon at the 5th position to which the amino group is bonded and
carbon at the 4th position to which a phenyl group is bonded are
asymmetric carbons, and can be used in various application
developments including optical activity.
[0044] Addition of an organic magnesium compound (Grignard
reagent), for example, PhMgBr and nBuMgBr, in a suitable amount in
the reaction of the lower stage also makes it possible to promote a
cyclization reaction.
[0045] By the way, 4,5-dihydro-1,3-thiazoles are materials that
have been known before, and are particularly used as important
intermediates for synthesis of active compounds based on
dihydrothiazole and thiazole in the agricultural chemical and
pharmaceutical industries (reference German patent No. DE10142749,
etc.) In the present invention, since an amino group is introduced
into the 5th position, the thiazole derivative is sufficiently
expected as a raw material for new application development, in
addition to the same applications of dihydrothiazole that has been
used so far.
[0046] In the above described reaction process, a thioformamide is
reacted and iodine is then further added thereto, thus a thiazole
derivative represented by the general formula (V) can be obtained.
As described above, when an aryl group is present at the 4th
position (a phenyl group in the general formula (V)),
dihydrothiazole is basically generated, but by adding iodine to the
reaction system, it is considered to proceed de-protonation. Among
thiazole derivatives thus obtained, at least one of R.sup.5 and
R.sup.6 shown in the general formula (V) is an aryl group that may
be substituted with one or more substituents selected from halogen,
hydroxy, lower alkyl, lower alkoxy, and halo lower alkyl, or a
heteroaromatic group that may be substituted with the same
substituents, and thus, the derivative shows fluorescence
emission.
##STR00007##
[0047] As reaction conditions at the time of iodine addition, a
thioformamide is added at the above described reaction temperature
(-78.degree. C. to room temperature) and then reacted while mixing
from about several minutes to several hours, thereafter adding
iodine so as to have a molar concentration of an equivalent mole to
3 mole ratios, preferably 1.5 to 2.5 mole ratios with respect to
the thioformamide, with keeping the reaction temperature. In
addition of iodine, solid iodine can be directly added, or iodine
can be once dissolved in a reaction solvent (e.g., tetrahydrofuran)
and added to a reaction system. When iodine is reacted for about
several minutes to several hours while stirring and the like after
addition, a desired thiazole derivative represented by the general
formula (V) having an aryl group at the 4th position can be
obtained.
[0048] By the way, an EL element utilizing electroluminescence has
characteristics such as having excellent impact resistance, since
it has high visibility because of self-luminescence and is a
complete solid-state element, and thus, such an EL element attracts
attention for utilization as a light emitting element in various
display devices. In particular, an organic EL element significantly
reduces an applied voltage, and besides, it has characteristics
such that miniaturization is easy and electric power consumption is
small. Huge quantities of compound groups having a diarylamino
group have been reported so far, and utilization as an organic EL
element is now widely studied. A thiazole derivative represented by
the above described general formula (V) has intensive fluorescence
emission particularly when R.sup.5 and R.sup.6 are diarylamino
groups. That is, a conjugated system of a diarylamino group extends
even to a thiazole ring and a substituent phenyl, in this compound
and, as a totally new electronic material, for example, a base
compound that can be used for an electron transfer layer in an
organic EL element can be created.
[0049] Next, a synthesis path of thiazole will be shown in the case
of using a compound having a pyridyl group in R.sup.2 as the above
described amino group-containing compound:
##STR00008##
[0050] Since there is no difference from the reactions that have
been already described until the upper and middle stages of the
above described reactions, the lower stage will be only described
herein. When nBuLi is acted on a thioamide having a pyridyl group
to thus form a dianion, and a thioformamide is reacted thereto,
although dihydrothiazole is once generated, de-protonation proceeds
due to a nitrogen atom in a pyridyl group, and
4-(2-pyridyl)thiazole is generated by dehydrogenation. Such
thiazole is useful as a functional compound (or a synthesis
intermediate thereof) such as an agricultural chemical, a medical
drug, a fungicide and a dye, and an electronic material, and in
recent years, it is attracting attention also as a light emitting
material for high-intensity brightness and colorization
(particularly, realization of red light emission) of an organic
EL.
[0051] An example using a thioamide bonded to the 2nd position of a
pyridyl group was shown in the above described reaction formula
(c), and a thioamide bonded to the 3rd or 4th position of a pyridyl
group may be used. However, use of a thioamide bonded to the 2nd
position of a pyridyl group is preferable since the final generated
product (general formula (I')) can be obtained at the highest
yield.
[0052] Some examples of the present invention will be shown below
in order to more specifically clarify the present invention.
Example 1
[0053] The whole scheme for a synthesis method of compound 3
(4,5-dihydro-2,4-diphenyl-5-dimethylaminothiazole) is shown below
as follows:
##STR00009##
Synthesis of compound 1 (N-phenylmethylbenzenecarbothioamide)
[0054] Benzaldehyde (10.1 mL, 0.1 mol) was added to a dimethyl
formamide (DMF: 50 mL) solution of benzylamine (12.0 mL, 0.11 mol)
at room temperature. Then, sulfur (3.52 g, 0.11 mol) was added
thereto and heated while stirring at 80 to 90.degree. C. for 6
hours. The reaction mixture solution was poured into ethyl ether
(50 mL) and the organic layer was washed with an aqueous solution
of saturated sodium hydrogen carbonate (200 mL) and hydrochloric
acid (35%, 10 mL). Furthermore, the organic layer was dried with
magnesium sulfate, filtrated and concentrated under reduced
pressure, and the residue was re-crystallized with hexane/methylene
chloride (1:1, 30 mL) to obtain 21.3 g (yield: 94%) of the compound
1 as a yellow solid.
Synthesis of Compound 3
[0055] The compound 1 (0.227 g, 1.0 mmol) was dissolved in THF (2.0
mL), and n-butyllithium-hexane solution (1.3 mL, 2.0 mmol) was
gradually added to this solution at 0.degree. C. After stirring for
5 minutes, N,N-dimethylthioformamide was added thereto at the same
temperature and stirring was further continued for 2.5 hours. Water
(10 mL) was added to the reaction mixture solution, and the organic
layer was extracted with diethyl ether (10 mL). The organic layer
was washed twice with water (10 mL), and a water tank was further
re-extracted with diethyl ether (5 mL). The organic layer collected
was dried with magnesium sulfate, filtrated, and concentrated under
reduced pressure, and the residue was purified by silica gel
chromatography (developing solvent;
Hexane:EtOAc:Et.sub.2N=5:1:0.01) to obtain
trans-4,5-dihydro-2,4-diphenyl-5-dimethylaminothiazole (0.14 g,
50%) as a light yellow solid.
[0056] Melting point at 89 to 91.degree. C.
[0057] A H-nuclear magnetic resonance spectrum and a
.sup.13C-nuclear magnetic resonance spectrum of the compound 3 were
measured, using JNM.alpha.-400 type manufactured by JEOL Ltd., at
25.degree. C. in deuterated chloroform, and the .sup.1H-nuclear
magnetic resonance spectrum was measured 8 times of the number of
integration, and the .sup.13C-nuclear magnetic resonance spectrum
was measured 100 to 200 times of the number of integration. Results
thereof are shown as follows.
(Trans-4,5-Dihydro-2,4-Diphenyl-5-Dimethylaminothiazole)
[0058] .sup.1H NMR (CDCl.sub.3) .delta.2.11 (s, 6H, NMe.sub.2),
5.11 (d, J=2.0 Hz, 1H, SCH), 5.6 (d, J=2.0 Hz, 1H, C.dbd.NCH),
7.08-7.19 (m, 5H, Ar), 7.27-7.35 (m, 3H, Ar), 7.90-7.92 (m, 2H,
Ar); .sup.13C NMR (CDCl.sub.3) .delta.40.0 (NMe.sub.2), 84.2 (SCH),
90.5 (C.dbd.NCH), 126.0, 127.6, 128.4, 128.5, 131.1, 133.5, 139.7,
168.7 (SCN)
[0059] IR data and MS data are also shown below together. IR (KBr)
2947, 1597, 1450, 1355, 1265, 1229, 1051, 1027, 834, 754, 687, 651,
566, 521 cm.sup.=1; MS (EI) m/z 282 (M.sup.+); HRMS (EI) Calcd for
C.sub.17H.sub.18N.sub.2S (M.sup.+) 282.1191. found: 282.1177.
Example 2
[0060] A mixing ratio, a temperature, a time and the like of each
compound were the same operations as in Example 1, but "stirring
was continued for 30 minutes and a phenyl magnesium bromide
(PhMgBr) THF solution (1.09 M, 1.83 mL, 2.0 mmol) was added at room
temperature and the mixture was stirred for 2 hours" instead of
adding N,N-dimethylthioformamide at the same temperature and then
continuing stirring for 2.5 hours. After that, operations were
performed in the same manner as in Example 1 to obtain
trans-4,5-dihydro-2,4-diphenyl-5-dimethylaminothiazole (0.235 g,
83%) as a light yellow solid. As shown in this example, addition of
PhMgBr makes it possible to promote a cyclization reaction.
Example 3
[0061] Regarding a synthesis example of each of the
dihydrothiazoles (3b to 3g) shown in Table 1 below, yields as well
as the compound 1 and thioformamide which were used are shown in
the same table. In addition, various conditions such as an amount
to be used of each compound (molar ratio), a temperature, and a
time are the same as in Example 2.
TABLE-US-00001 TABLE 1 1 (Thioamide) Thioformamide 3 (Thiazole
derivative) Yields ##STR00010## ##STR00011## ##STR00012## 73%
##STR00013## ##STR00014## ##STR00015## 24% ##STR00016##
##STR00017## ##STR00018## 19% ##STR00019## ##STR00020##
##STR00021## 60% ##STR00022## ##STR00023## ##STR00024## 36%
##STR00025## ##STR00026## ##STR00027## 38%
[0062] Measurement results such as a nuclear magnetic resonance
spectrum for each dihydrothiazole shown in Table 1 are shown
below.
(Trans-4,5-dihydro-2-(4-methoxyphenyl)-4-phenyl-5-dimethylaminothiazole
(3b); yellow oil)
[0063] IR (neat) 2951, 2833, 2786, 1605, 1508, 1254, 1170, 1031,
948, 837, 698, 657, 566 cm.sup.-1; .sup.1HNMR (CDCl.sub.3)
.delta.2.19 (s, 6H, NMe.sub.2), 3.77 (s, 3H.sub.2OMe), 5.16 (d,
J=2.0 Hz, 1H, SCH), 5.61 (d, J=2.0 Hz, 1H, C.dbd.NCH), 6.88-6.90
(d, J=8.8 Hz, 2H, Ar), 7.19-7.26 (m, 5H, Ar), 7.92-7.94 (m, 2H,
Ar); .sup.13C NMR (CDCl.sub.3) .delta.40.0 (NMe.sub.2), 55.2 (OMe),
84.2 (SCH), 90.4 (C.dbd.NCH), 113.6, 126.1, 126.2, 127.5, 128.5,
130.1, 140.0, 162.0, 168.0 (SCN); MS (EI) m/z 312 (M.sup.+); HRMS
(EI) Calcd for C.sub.28H.sub.20N.sub.2OS (M.sup.+) 312.1296. found:
312.1292.
(Trans-2,4-dihydro-2-isopropyl-4-phenyl-5-dimethylaminothiazole
(3c); yellow liquid)
[0064] IR (neat) 2966, 1614, 1454, 1287, 1044, 873, 835, 753, 699,
598 cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta.1.28 (dd, J=6.8 Hz,
2.0 Hz, 6H, CH(CH.sub.3).sub.2), 2.13 (s, 6H, NMe.sub.2), (sept,
J=6.8 Hz, 1H, CH(CH.sub.3).sub.2), 4.99 (d, J=2.0 Hz, 1H, SCH),
5.33-5.34 (d, J=2.0 Hz, 1H, C.dbd.NCH), 7.16-7.27 (m, 5H, Ar);
.sup.13C NMR (CDCl.sub.3) .delta.21.6 (CH(CH.sub.3).sub.2), 35.0
(CH(CH.sub.3).sub.2), 40.0 (NMe.sub.2), 83.5 (SCH), 89.7
(C.dbd.NCH), 126.0, 127.6, 128.6, 140.0, 178.6 (SCN); MS (EI) m/z
248 (M.sup.+); HRMS (EI) Calcd for C.sub.24H.sub.20N.sub.2S
(M.sup.+) 248.1347. found: 248.1354.
(Trans-2,4-dihydro-2-(2-pyridyl)-4-phenyl-5-dimethylaminothiazole
(3d); orange oil)
[0065] IR (neat) 3290, 3059, 2951, 2788, 1599, 1494, 1467, 1435,
1296, 1280, 1176, 1149, 1045, 1025, 996, 958, 836, 789, 743, 698,
537 cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta.2.11 (s, 6H,
NMe.sub.2), 5.14-5.15 (d, J=2.0 Hz, 1H, SCH), 5.63 (d, J=2.0 Hz,
1H, C.dbd.NCH), 7.18-7.22 (m, 2H, Ar), 7.24-7.25 (m, 2H, Ar),
7.30-7.37 (m, 2H, Ar) 7.68-7.73 (td, J=7.8 Hz, 2.0 Hz, 1H, Ar),
8.11-8.13 (d, J=8.29 Hz, 1H, Ar), 8.64-8.66 (d, J=8.29 Hz, 1H, Ar);
.sup.13C NMR (CDCl.sub.2) .delta.40.1 (NMe.sub.2), 84.9 (SCH), 88.9
(C.dbd.NCH), 121.9, 125.6, 126.2, 127.8, 128.7, 136.6, 139.6,
149.4, 151.3, 170.9 (SCN); MS (EI) m/z 283 (M.sup.+); HRMS (EI)
Calcd for C.sub.26H.sub.17N.sub.3S (M.sup.+) 283.1143. found:
283.1170.
(Trans-4,5-dihydro-2-(4-fluorophenyl)-4-phenyl-5-dimethylaminothiazole
(3e); orange oil)
[0066] IR (neat) 3062, 2949, 1603, 1506, 1451, 1234, 1154, 1028,
949, 842, 753, 698, 657, 562 cm.sup.-1; .sup.1H NMR (CDCl.sub.3)
.delta.2.20 (s, 6H, NMe.sub.2), 5.22 (d, J=2.0 Hz, 1H, SCH), 5.63
(d, J=2.0 Hz, 1H, C.dbd.NCH), 7.05-7.10 (t, J=8.5 Hz, 2H, Ar),
7.23-7.31 (m, 5H, Ar), 7.95-8.00 (m, 2H, Ar); C NMR (CDCl.sub.2)
.delta. 40.1 (NMe.sub.2), 84.3 (SCH), 91.1 (C.dbd.NCH), 126.0,
127.6, 128.4, 128.5, 131.1, 133.5, 139.7, 168.7 (SCN); F NMR
(CDCl.sub.2) .delta. -108.8; MS (EI) m/z 300 (M.sup.+); HRMS (EI)
Calcd for C.sub.22H.sub.17FN.sub.2S (M.sup.+) 300.1096. found:
300.1120.
(Trans-2,4-dihydro-2-tertiary
butyl-4-phenyl-5-dimethylaminothiazole (3f); yellow liquid)
[0067] IR (neat) 2965, 2360, 1611, 1451, 1362, 1042, 1002, 751, 698
cm.sup.-1; .sup.1H NMR (CDCl.sub.2) .delta.1.39 (s, 9H,
CH(CH).sub.3), 2.21 (s, 6H, NMe.sub.2), 5.02-5.03 (d, J=1.5 Hz, 1H,
SCH), 5.46-5.47 (d, J=1.5 Hz, 1H, C.dbd.NCH), 7.22-7.35 (m, 5H,
Ar); C NMR (CDCl.sub.2) .delta.29.6 (CH(CH).sub.3), 38.9
(CH(CH).sub.3), 40.0 (NMe.sub.2), 83.8 (SCH), 89.5 (C.dbd.NCH),
125.9, 127.5, 128.5, 139.9, 181.5 (SCN); MS (EI) m/z 262 (M.sup.+);
HRMS (EI) Calcd for C.sub.15H.sub.22N.sub.2S (M.sup.+) 262.1504.
found: 262.1500.
(Trans-4,5-dihydro-2,4-diphenyl-5-morpholinothiazole (3g))
[0068] (m.p. 92-94.degree. C.): IR (KBr) 2854, 1598, 1450, 1269,
1231, 1137, 1113, 945, 752, 565 cm.sup.-1; .sup.1H NMR (CDCl.sub.3)
.delta. 2.47-2.52 (m, 4H, N(CH.sub.2).sub.2), 3.67-3.69 (m, 4H,
O(CH.sub.2).sub.2), 5.08-5.09 (d, J=2.0 Hz, 1H, SCH), 5.68 (d,
J=2.0 Hz, 1H, C.dbd.NCH), 7.18-7.29 (m, 5H, Ar), 7.36-7.41 (m, 3H,
Ar), 7.95-7.98 (m, 2H, Ar); .sup.13C NMR (CDCl.sub.2) .delta.47.9
(N(CH.sub.2).sub.2), 66.3 (O(CH.sub.2).sub.2), 83.6 (SCH), 89.1
(C.dbd.NCH), 126.2, 127.8, 128.5, 128.6, 128.7, 131.4, 133.3,
139.4, 168.8 (SCN); MS (EI) m/z 324 (M.sup.+); HRMS (EI) Calcd for
C.sub.19H.sub.20N.sub.2OS (M.sup.+) 324.1296. found: 324.1269.
Example 4
[0069] The whole scheme for a synthesis method of the compound 4
(2-phenyl-4-(2-pyridyl)thiazole) is shown below as follows:
##STR00028##
Synthesis of compound
1'(N-(2-pyridylmethyl)benzenecarbothioamide)
[0070] Benzaldehyde (2.03 mL, 0.02 mol) was added to a dimethyl
formamide (DMF: 8 mL) solution of pyridylmethylamine (2.22 mL,
0.022 mol) at room temperature. Sulfur (0.71 g, 0.022 mol) was then
added thereto and the mixture was heated while stirring at 80 to
90.degree. C. for 6 hours. The reaction mixture solution was poured
into ethyl ether (20 mL), and the organic layer was washed with an
aqueous solution of saturated sodium hydrogen carbonate (50 mL).
Further, the organic layer was dried with magnesium sulfate,
filtrated, and concentrated under reduced pressure, and the residue
was purified by silica gel column chromatography (developing
solvent; Hexane: EtOAc=2:1 to 1:2) to obtain 3.33 g (yield: 73%) of
the compound 1 as a yellow solid.
Synthesis of Compound 4
[0071] The compound 1' (0.228 g, 1.0 mmol) was dissolved in THF
(2.0 mL), and an n-butyllithium-hexane solution (1.3 mL, 2.0 mmol)
was gradually added to this solution at 0.degree. C. After stirring
for 5 minutes, N,N-dimethylthioformamide was added thereto at the
same temperature and stirring was further continued for 3 hours.
Water (10 mL) was added to the reaction mixture solution, and the
organic layer was extracted with diethyl ether (10 mL). The organic
layer was washed twice with water (10 mL), and a water tank was
further re-extracted with diethyl ether (5 mL). The organic layer
collected was dried with magnesium sulfate, filtrated, and
concentrated under reduced pressure, and the residue was purified
by silica gel chromatography (developing solvent;
Hexane:EtOAc:Et.sub.2N=5:1:0.01) to obtain
2-phenyl-4-(2-pyridyl)thiazole (0.149 g, 62%) as a light orange
solid.
[0072] Melting point at 107 to 109.degree. C.
[0073] The same various measurements were performed also on the
obtained 2-phenyl-4-(2-pyridyl)thiazole, and results thereof are
shown below.
[0074] IR (KBr) 2362, 1587, 1474, 1420, 1057, 991, 754, 684, 667,
591 cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta. 7.07-7.11 (m, 1H,
Ar), 7.28-7.35 (m, 3H, Ar), 7.62-7.66 (td, J=7.6 Hz, 7.8 Hz, 1H,
Ar), 7.91-7.93 (m, 2H, Ar), 7.97 (s, 1H, SCH), 8.14-8.16 (d, J=7.8
Hz, 1H, Ar), 8.50-8.51 (d, J=3.9 Hz, 1H, Ar); .sup.13C NMR
(CDCl.sub.3) .delta.116.8, 121.2, 122.7, 126.5, 128.8, 130.0,
133.5, 136.8, 149.3, 152.5, 156.0, 167.9 (SCN); MS (EI) m/z 238
(M.sup.+); HRMS (EI) Calcd for C.sub.14H.sub.10N.sub.2S (M.sup.+)
238.0565. found: 238.0572.
Example 5
[0075] Regarding a synthesis example of each of the pyridyl
thiazoles (4b to 4h) shown in Table 2 below, yields as well as the
compound 1 that was used are shown in the same table. In addition,
various conditions such as an amount to be used of each compound
(molar ratio), a temperature, and a time are the same as in Example
4.
TABLE-US-00002 TABLE 2 1' (Thioamide) 4 (Thiazole derivative)
Yields ##STR00029## ##STR00030## 46% ##STR00031## ##STR00032## 38%
##STR00033## ##STR00034## 85% ##STR00035## ##STR00036## 46%
##STR00037## ##STR00038## 37% ##STR00039## ##STR00040## 64%
##STR00041## ##STR00042## 24%
[0076] Measurement results such as a nuclear magnetic resonance
spectrum for each pyridyl thiazole shown in Table 2 are shown
below.
(2,4-di(2-pyridyl)thiazole (4b))
[0077] .sup.1H NMR (CDCl.sub.3) .delta.7.12-7.16 (m, 1H, Ar),
7.20-7.24 (m, 1H, Ar), 7.67-7.72 (m, 2H, Ar), 8.11-8.16 (m, 2H,
Ar), 8.20-8.22 (d, J=7.8 Hz, 1H, Ar), 8.52-8.55 (m, 2H, Ar).
(2-thiophen-4-(2-pyridyl)thiazole (4c))
[0078] (m.p. 114-115.degree. C.): IR (KBr) 3126, 1587, 1473, 1424,
1227, 1052, 830, 767, 698 cm.sup.-1; .sup.1H NMR (CDCl.sub.3)
.delta.7.09-7.10 (m, 1H, Ar), 7.22-7.25 (m, 1H, Ar), 7.42-7.43 (dd,
J=4.9 Hz, 1.0 Hz, 1H, Ar), 7.56-7.58 (dd, J=3.9 Hz, 1.0 Hz, 1H,
Ar), 7.76-7.80 (m, 1H, Ar), 8.04 (s, 1H, SCH), 8.23-8.25 (d, J=7.8
Hz, 1H,), 8.63-8.64 (m, 1H, Ar); .sup.13C NMR (CDCl.sub.3)
.delta.116.0, 121.3, 122.8, 126.6, 127.6, 127.7, 136.8, 137.2,
149.3, 152.2, 155.6, 161.5 (SCN); MS (EI) m/z 244 (M.sup.+); HRMS
(EI) Calcd for C.sub.12H.sub.8N.sub.2S.sub.2 (M.sup.+) 244.0129.
found: 244.0105.
(2-(4-methoxyphenyl)-4-(2-pyridyl)thiazole (4d))
[0079] (m.p. 100-103.degree. C.): IR (KBr) 3085, 2836, 1605, 1476,
1306, 1247, 1180, 1026, 834, 776, 713 cm.sup.-1; .sup.1H NMR
(CDCl.sub.3) .delta.3.76 (s, 1H, OMe), 6.85-6.89 (d, J=8.8 Hz, 2H,
Ar), 7.11-7.17 (m, 1H, Ar), 7.66-7.70 (td, J=7.8 Hz, 2.0 Hz, 1H,
Ar), 7.86-7.90 (d, J=8.8 Hz, 2H, Ar), 7.93 (s, 1H, SCH), 8.15-8.17
(d, J=7.8 Hz, 1H, Ar), 8.52-8.54 (m, 1H, Ar); .sup.13C NMR
(CDCl.sub.3) .delta.55.3 (CH.sub.3), 114.2, 116.0, 121.2, 122.7,
126.5, 128.0, 136.9, 149.3, 152.6, 155.7, 161.1, 167.9 (SCN); MS
(EI) m/z 268 (M.sup.+); HRMS (EI) Calcd for
C.sub.15H.sub.12N.sub.2OS (M.sup.+) 268.0670. found: 268.0663.
(2-(4-fluorophenyl)-4-(2-pyridyl)thiazole (4e))
[0080] (m.p. 140-144.degree. C.): IR (KBr) 3103, 1588, 1519, 1477,
1229, 1060, 994, 832, 751, 581, 505 cm.sup.-1; .sup.1H NMR
(CDCl.sub.3) .delta.7.12-7.18 (t, J=8.8 Hz, 2H, Ar), 7.22-7.25 (m,
1H, Ar), 7.76-7.81 (td, J=7.82 Hz, 1H, Ar), 7.99-8.04 (m, 2H, Ar),
8.08 (s, 1H, SCH), 8.23-8.25 (d, J=7.81 Hz, 1H, Ar), 8.63-8.64 (m,
1H, Ar); .sup.13C NMR (CDCl.sub.3) .delta.115.8, 116.0, 116.8,
121.2, 122.8, 129.9, 129.9, 136.9, 149.3, 152.4, 156.0, 162.6
165.1, 166.8 (SCN); .sup.19F NMR (CDCl.sub.3) .delta.-20.0; MS (EI)
m/z 256 (M.sup.+); HRMS (EI) Calcd for C.sub.14H.sub.9FN.sub.2S
(M.sup.+) 256.0470. found: 256.0474.
(2-(4-trifluoromethylphenyl)-4-(2-pyridyl)thiazole (4f))
[0081] (m.p. 123-127.degree. C.): IR (KBr) 2361, 1588, 1475, 1407,
1327, 1162, 1110, 1068, 846, 764, 673, 608 cm.sup.-1; .sup.1H NMR
(CDCl.sub.3) .delta.7.13-7.17 (m, 1H, Ar), 7.59-7.91 (d, J=8.3 Hz,
2H, Ar), 7.66-7.71 (td, J=7.6 Hz, 1H, Ar), 8.01-8.03 (m, 3H, Ar),
8.13-8.15 (d, J=7.8 Hz, 1H, Ar), 8.52-8.54 (d, J=4.9 Hz, 1H, Ar);
.sup.13C NMR (CDCl.sub.3) .delta.117.8, 121.3, 122.5, 123.0, 125.8,
125.9, 126.7, 131.4, 131.7, 136.6, 136.9, 149.4, 152.2, 156.6,
166.0 (SCN); .sup.19F NMR (CDCl.sub.3) .delta.-63.1; MS (EI) m/z
306 (M.sup.+); HRMS (EI) Calcd for C.sub.15H.sub.9F.sub.3N.sub.2S
(M.sup.+) 306.0439. found: 306.0428.
(2-isopropyl-4-(2-pyridyl)thiazole (4g))
[0082] Orange liquid: IR (neat) 2967, 1588, 1496, 1420, 1331, 1051,
754, 621 cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta.1.35-1.37 (d,
J=7.3 Hz, 6H, CH(CH.sub.3).sub.2), 3.25-3.35 (sept, J=6.9 Hz, 1H,
CH(CH.sub.3).sub.2), 7.08-7.11 (m, 1H, Ar), 7.62-7.67 (td, J=7.6
Hz, 1H, Ar), 7.84 (s, 1H, SCH), 8.02-8.04 (d, J=7.84 Hz, 1H, Ar),
8.51-8.52 (d, J=4.9 Hz, 1H, Ar) .sup.13C NMR (CDCl.sub.3)
.delta.23.1 (CH(CH.sub.3).sub.2), 33.4 (CH(CH.sub.3).sub.2), 115.6,
121.1, 122.4, 136.8, 149.3, 152.8, 154.5, 178.0 (SCN); MS (EI) m/z
204 (M.sup.+); HRMS (EI) Calcd for C.sub.11H.sub.12N.sub.2S
(M.sup.+) 204.0721. found: 204.0691.
(2-tertiary butyl-4-(2-pyridyl)thiazole (4h))
[0083] Orange oil: IR (neat) 2961, 2925, 1588, 1495, 1463, 1065,
994, 754 cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta.1.42 (s, 9H,
C(CH.sub.3).sub.3), 7.10-7.19 (m, 1H, Ar), 7.65-7.69 (td, J=7.8 Hz,
1H, Ar), 7.85 (s, 1H, SCH), 8.08-8.10 (dd, J=7.8 Hz, 1.0 Hz, 1H,
Ar), 8.51-8.52 (d, J=7.8 Hz, 1H, Ar); .sup.13C NMR (CDCl.sub.3)
.delta.30.9 (C(CH.sub.3).sub.3), 37.8 (C(CH.sub.3).sub.3), 115.6,
121.3, 122.4, 136.8, 149.3, 153.0, 154.4, 181.1 (SCN); MS (EI) m/z
218 (M.sup.+); HRMS (EI) Calcd for C.sub.12H.sub.14N.sub.2S
(M.sup.+) 218.0878. found: 218.0857.
Example 6
[0084] The whole scheme for a synthesis method of the compound 5
(2-(4-methoxyphenyl)-4-phenyl-5-diphenylaminothiazole) by a
reaction of adding iodine is then shown as follows:
##STR00043##
[0085] Specifically, the compound 1 shown in Example 1 was
synthesized, the compound 1 (0.257 g, 1.0 mmol) was then dissolved
in THF (2.0 mL), a BuLihexane solution (1.43 M, 1.40 mL, 2.0 mmol)
was added to this solution at 0.degree. C., and the mixture was
stirred for 5 minutes. N,N-diphenylthioformamide (0.213 g, 1.0
mmol) was added to the solution at 0.degree. C., and the mixture
was stirred for 30 minutes. Thereto was added iodine (0.512 g, 2.0
mmol) at 0.degree. C., and stirring was continued for 2 hours. The
reaction mixture solution was poured into a saturated solution of
ammonium chloride and extracted with methylene chloride. The
organic layer was dried with magnesium sulfate and concentrated.
The residue was purified by silica gel column chromatography to
obtain 2-(4-methoxyphenyl)-4-phenyl-5-diphenylaminothiazole at a
yield of 26% as a yellow solid.
[0086] Measurement results such as a nuclear magnetic resonance
spectrum for the compound 5 are shown below. A fluorescence
spectrum (solid line) by a fluorescence spectrometer of the
compound is shown in FIG. 1. A fluorescent intensity is a value
when that of rhodamine B was assumed to be 100 in the FIGURE. In
this FIGURE, a fluorescence spectrum (dashed line) of
2-(4-methoxyphenyl)-4-phenyl-5-dimethylaminothiazole is shown for
comparison, and an effect in the case where a diphenylamino group
was used as a substituent is prominently shown.
(2-(4-methoxyphenyl)-4-phenyl-5-diphenylaminothiazole)
[0087] mp.: 152-155.degree. C.; IR (KBr) 3064, 2926, 2839, 1602,
1515, 1490, 1415, 1341, 1290, 1245, 1173, 1029, 975, 838, 748, 514
cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta.3.75 (s, 3H, OMe), 6.86
(d, J=8.8 Hz, 2H, Ar), 6.90 (t, J=7.3 Hz, 2H, Ar), 7.05-7.07 (m,
4H, Ar), 7.10-7.20 (m, 7H, Ar), 7.82 (d, J=8.8 Hz, 2H, Ar),
7.85-7.88 (m, 2H, Ar); .sup.13C NMR (CDCl.sub.3) .delta.55.4 (OMe),
114.1, 121.3, 122.9, 127.0, 127.4, 127.7, 127.9, 128.2, 129.2,
133.4, 138.9, 146.5, 148.6, 161.2, 163.6 (SC.dbd.N); MS (EI) m/z
434 (M.sup.+); HRMS (EI) Calcd for C.sub.28H.sub.22N.sub.2OS
(M.sup.+) 434.1453. found: 434.1437.
Example 7
[0088] The same operations were performed except for using
N-phenyl-N-methylthioformamide (0.119 g, 1.0 mmol) in place of
N,N-diphenylthioformamide in Example 6, to obtain
2-(4-methoxyphenyl)-4-phenyl-5-(N-phenyl-N-methylamino) thiazole at
a yield of 19% as a yellow solid.
(2-(4-methoxyphenyl)-4-phenyl-5-(N-phenyl-N-methylamino)
thiazole)
[0089] mp.: 100-101.degree. C.; IR(KBr) 2939, 1904, 1596, 1491,
1298, 1258, 1221, 1168, 1136, 1111, 1028, 977, 833, 751, 701
cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta.3.10 (s, 3H, NMe), 3.74
(s, 3H, OMe), 6.76-6.87 (m, 5H, Ar), 7.12-7.21 (m, 3H, Ar), 7.26
(t, J=7.3 Hz, 2H, Ar), 7.83 (d, J=9.4 Hz, 2H, Ar), 7.90 (d, J=7.32
Hz, 2H, Ar); .sup.13C NMR (CDCl.sub.3) .delta.40.3 (NMe), 55.3
(OMe), 114.1, 114.2, 119.3, 127.1, 127.3, 127.7, 127.9, 128.5,
129.1, 133.8, 141.0, 148.3, 148.4, 161.1, 163.2 (SC.dbd.N); MS (EI)
m/z 372 (M.sup.+).
INDUSTRIAL APPLICABILITY
[0090] The thiazole derivative of the present invention can be
simply produced from easily available raw materials without
undergoing a complicated synthesis path by the production process
of the present invention. For a synthesized product, specifying a
substituent of a starting substance makes it possible to obtain a
generated product selectively, and also, a totally novel compound
that has never existed so far can be easily obtained. Therefore,
the obtained thiazole derivative can be utilized as a material (and
an intermediate) of a novel compound useful as medical drugs and
agricultural chemicals, etc.
* * * * *